The first embodiment of the present invention relates to mono- or polyenic carboxylic acid derivatives or physiologically acceptable salts thereof or drugs containing the mono- or polyenic carboxylic acid derivatives or the physiologically
The second embodiment of the present invention relates to heterocyclic compounds. More particularly, it relates to novel heterocyclic compounds which are extremely effective in the prevention and treatment of diseases.
Retinoic acid (vitamin A acid, abbreviation: RA) is an essential substance to the growth and life support of humans and other mammals. It has been known that retinoic acid acts as a morphogenesis factor in ontogenesis and functions variously in the differentiation and proliferation of adults. For example, it has been known that the acid participates in the cornification, formation of hairs, functions of sebaceous glands, and so on with respect to the epidermis, in the metabolism of bones and cartilages with respect to the connective tissues, in the regulation of immune functions with respect to the immune system, in the differentiation of nerve cells with respect to the nervous system, in the differentiation and proliferation of blood cells with respect to the hemic system, and in the secretion of thyroid hormones, parathyroid hormones and so on and the regulation of the functions thereof in target organs, thus taking part in the mineral metabolism and the basal metabolism. These various physiological actions of retinoic acid are exhibited by directly controlling gene expression through retinoid receptor (RARs, RXRs) family present in cell nuclei. With respect to retinoic acid, there are not only deficiencies but also excesses thereof such as abnormality in cornification, depilation, metabolic disorder of bones and cartilages, and so on. Further, the abnormality of retinoid receptors has recently been found in acute promyelocytic leukemia, head and neck squamous cell carcinoma, lung cancer and so on, and the participation of retinoic acid in the sideration and evolution thereof has been reported.
In order to elucidate detailed mechanisms of these various actions of retinoids and to find the possibility for clinical application thereof, it has great significance to develop compounds antagonistic against retinoids. Although TD-550 and TD-560 (Cell Biol. Rev., 25, 209(1991)) and Ro41-5253 (Proc. Natl. Acad. Sci., U.S.A., 89, 7129 (1992)) have already been known as compounds antagonistic against retinoids, they are thought to be poor in both the ability to bind RARs and antagonism against retinoids.
Meanwhile, RARs and RXRs are known as retionid receptors, which are members of steroid/thyroid receptor superfamily present in cell nuclei. Known receptors belonging to this superfamily include estrogen receptors (ER), thyroid hormone receptors (TR), vitamin D3 receptors (D3R) and steroid hormone receptors. With respect to RXRs, there are xcex1-, xcex2- and xcex3-subtypes, and the ligand thereof has recently been identified with 9-cis RA. Further, it has been found that RXRs have the physiological property of forming heterodimers together with RXRs, TR, D3R or other receptors. Thus, it is being elucidated that RXRs act synergistically with their respective inherent ligands to take great part in the expression of the functions of retinoic acid, vitamin D3 or thyroid hormones through such heterodimers. In order to elucidate detailed mechanisms of these various actions of RXRs and to find the possibility for clinical application thereof, it has great significance to develop compounds binding to RXRs.
In view of the above actual circumstances, the inventors of the present invention have intensively studied to find that mono- or polyenic carboxylic acid derivatives which will be described below exhibit agonism for RXRs and are useful as drugs. As the prior art, although JP-A-2-76862 and EP 0568898 disclose monoenic carboxylic acid derivatives and polyenic carboxylic acid derivatives these derivatives are different from the compounds of the present invention in both chemical structure and drug effect.
Further, the inventors of the present invention have found that heterocyclic compounds described below exhibit extremely high ability to bind RARs and antagonism against retinoids, thus accomplishing the present invention.
For example, JP-A-2-240058 discloses heterocyclic compounds which exhibit such a function of agonist and are improved in the adverse reaction due to retinoid excess. However, these compounds are different from the compounds of the present invention in both chemical structure and drug effect.
The first embodiment of the present invention relates to mono- or polyenic carboxylic acid derivatives represented by the formula (1-I) or physiologically acceptable salts thereof:
Zxe2x80x94(CR3xe2x95x90CR2)nxe2x80x94COOR1xe2x80x83xe2x80x83(1-I)
[wherein
R1 is hydrogen or a carboxyl-protecting group; R2 and R3 are each independently hydrogen atom, halogen, linear lower alkyl, branched lower alkyl, linear lower alkoxy, branched lower alkoxy or aryl; n is an integer of 1 to 3; nR2""s or nR3""s may be the same or different from one another; and
Z is a group represented by the general formula (1-III) or (1-IV): 
{wherein A, B and D are each carbon, nitrogen, sulfur or oxygen, with the carbon or nitrogen atom optionally bearing a substituent; X1 and Y1 are each independently hydrogen, xe2x80x94NR4R5, xe2x80x94CR6R7R8, xe2x80x94OR9, xe2x80x94SR10, xe2x80x94S(xe2x86x92O)R11 or xe2x80x94S(xe2x86x92O)2R12 (wherein R4 and R5 are each independently hydrogen, linear lower alkyl, branched lower alkyl or cycloalkyl; R6, R7 and R8 are each independently hydrogen, linear lower alkyl or branched lower alkyl; and R9, R10, R11 and R12 are each independently hydrogen, linear lower alkyl or branched lower alkyl, with the proviso that when A or B is a carbon atom optionally bearing a substituent, R4 or R5 together with the substituent of A or B may form a ring), or alternatively X1 and Y1 together with the carbon atoms to which they are bonded may form an optionally substituted, saturated or unsaturated ring which may contain oxygen, sulfur and/or nitrogen, and the substituents on the saturated or unsaturated ring may be united to form a saturated or unsaturated ring which may contain oxygen, sulfur and/or nitrogen;
E is a carbon or nitrogen; F and G are each independently carbon, nitrogen, sulfur or oxygen, with the carbon or nitrogen atom optionally bearing a substituent; and X2 and Y2 are each independently hydrogen, xe2x80x94NR13R14, xe2x80x94CR15R16R17, xe2x80x94OR18, xe2x80x94SR19, xe2x80x94S(xe2x86x92O)R20 or xe2x80x94S(xe2x86x92O)2R21 (wherein R13 and R14 are each independently hydrogen, linear lower alkyl, branched lower alkyl or cycloalkyl; R15, R16 and R17 are each independently hydrogen, linear lower alkyl or branched lower alkyl; and R18, R19, R20 and R21 are each independently hydrogen, linear lower alkyl or branched lower alkyl), or alternatively X2 and Y2 may be united to form an optionally substituted, saturated or unsaturated ring which may contain oxygen, sulfur and/or nitrogen;
X3 and Y3 are each independently hydrogen, linear or branched lower alkyl, linear or branched lower alkoxy, cycloalkyl, aryl, heteroaryl, fluoroalkyl or halogeno; and
the symbol . . .   represents a single bond or a double bond}, with the proviso that the cases wherein Z is 
(wherein F and G are each as defined above) are excepted].
Preferable compounds of the present invention include mono- and polyenic carboxylic acid derivatives and physiologically acceptable salts thereof as described above wherein Z is a group represented by the formula: 
[wherein Ra, Rb, Rc and Rd are each independently hydrogen, linear or branched lower alkyl, linear or branched lower alkoxy, cycloalkyl, aryl, heteroaryl, fluoroalkyl or halogeno, or alternatively two of Ra, Rb, Rc and Rd may be united to form an optionally substituted, saturated or unsaturated ring which may contain oxygen, sulfur and/or nitrogen; Raxe2x80x2 and Rbxe2x80x2 are each independently hydrogen, linear or branched lower alkyl, linear or branched lower alkoxy, cycloalkyl, aryl, heteroaryl or fluoroalkyl; m is a number of 0 to 3; mxe2x80x2 is 0 or 1; and W is  greater than NRe,  greater than CReRf,  greater than SRg,  greater than S(xe2x86x92O),  greater than S(xe2x86x92O)2, O, N, CRe or S (wherein Re, Rf and Rg are each independently hydrogen, linear or branched lower alkyl, linear or branched lower alkoxy, cycloalkyl, aryl, heteroaryl, fluoroalkyl or halogeno), with the proviso that both the W""s in each group may be the same or different from each other].
Further, preferable compounds of the present invention include mono- and polyenic carboxylic acid derivatives and physiologically acceptable salts thereof as described above, wherein Z is a group represented by the formula: 
The carboxyl-protecting group as defined for R1 in the present invention includes lower alkyl groups such as methyl, ethyl and propyl.
The term xe2x80x9clinear lower alkylxe2x80x9d used in the definition of R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, R18, R19, R20, R21, Ra, Rb, Rc, Rd, Raxe2x80x2, Rbxe2x80x2, Re, Rf, Rg, X3 and Y3 refers to linear C1-C6 alkyl, examples of which include methyl, ethyl, propyl, butyl, amyl and pentyl. Among them, methyl, ethyl and propyl are preferable. The term xe2x80x9cbranched lower alkylxe2x80x9d used therein refers to isoproyl, isobutyl, sec-butyl, tert-butyl, amyl, isopentyl, neopentyl or the like, with isopropyl being preferable.
The term xe2x80x9clinear lower alkoxyxe2x80x9d used in the definition of R2, R3, Ra, Rb, Rc, Rd, Raxe2x80x2, Rbxe2x80x2, Re, Rf, Rg, X3 and Y3 refers to linear C1-C6 alkoxy, and examples thereof include methoxy, ethoxy, n-propoxy and n-butoxy. The term xe2x80x9cbranched lower alkoxyxe2x80x9d used therein refers to isopropoxy, sec-butoxy or the like. The term xe2x80x9ccycloalkylxe2x80x9d used in the definition of R4, R5, R13, R14, Ra, Rb, Rc, Rd, Raxe2x80x2, Rbxe2x80x2, Re, Rf, Rg, X3 and Y3 refers to C3-C7 cycloalkyl, and examples thereof include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. Further, the term xe2x80x9chalogenoxe2x80x9d used in this description refers to fluoro, chloro or bromo.
The aryl as defined for Ra, Rb, Rc, Rd, Raxe2x80x2, Rbxe2x80x2, Re, Rf, Rg, X3 and Y3includes phenyl and so on; the heteroaryl as defined therefor includes furyl and so on; and the fluoroalkyl as defined therefor includes trifluoromethyl and so on.
Further, n is an integer of 1 to 3, with the cases wherein n is 3 being most desirable.
Preferable examples of the compounds represented by the formula (1-I) include the following compounds: 
Further, the present invention relates also to mono- or polyenic carboxylic acid derivatives represented by the general formula (1-V) or physiologically acceptable salts thereof: 
[wherein R1 is hydrogen or a protecting group; R2, R3, R4, R5 and R6 are each independently hydrogen, halogeno, linear lower alkyl, branched lower alkyl, linear lower alkoxy or branched lower alkoxy; X and Y are each independently xe2x80x94NR7R8, xe2x80x94CR9R10R11, xe2x80x94OR12, xe2x80x94SR13, xe2x80x94S(xe2x86x92O)R14, or xe2x80x94S(xe2x95x90O)2R15 (wherein R7 and R8 are each independently hydrogen, linear lower alkyl, branched lower alkyl or cycloalkyl; R9, R10 and R11 are each independently hydrogen, linear lower alkyl or branched lower alkyl; and R12, R13, R14 and R15 are each independently hydrogen, linear lower alkyl or branched lower alkyl, or alternatively R7 or R8 together with R4 or R6 may form a ring), or alternatively X and Y together with the carbon atoms to which they are bonded may form a ring which may contain a double bond; A, B and D are each carbon, nitrogen, sulfur or oxygen and D may be nil; n is an integer of 1 to 3; and the broken line moiety represents a single bond or a double bond].
Preferable examples of the above compounds according to claim 1 include mono- and polyenic carboxylic acid derivatives represented by the general formula (1-VI) and physiologically acceptable salts thereof: 
[wherein X and Y are each independently xe2x80x94NR7R8 or xe2x80x94CR9R10R11 (wherein R7 and R8 are each independently hydrogen, linear lower alkyl, branched lower alkyl or cycloalkyl; R9, R10 and R11 are each independently hydrogen, linear lower alkyl or branched lower alkyl; and R12, R13 , R4 and R15 are each independently hydrogen, linear lower alkyl or branched lower alkyl, or alternatively R7 or R8 together with R4 or R6 may form a ring); Z is xe2x80x94(CR16R17)1xe2x80x94, xe2x80x94(CR18)mxe2x95x90 or xe2x80x94CR19xe2x95x90CR20)pxe2x80x94 (wherein R16, R17, R18, R19 and R20 are each independently hydrogen or lower alkyl; and l, m and p are each an integer of 1 to 4); n is an integer of 1 to 3; and the broken line moiety represents a single bond or a double bond].
The term xe2x80x9clinear lower alkylxe2x80x9d used in the definition of R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12 , R13, R14 and R15 in the present invention refers to linear C1-C6 alkyl, examples of which include methyl, ethyl, propyl, butyl, amyl and pentyl. Among them, ethyl, ethyl and propyl are preferable. The term xe2x80x9cbranched lower alkylxe2x80x9d used therein refers to isopropyl, isobutyl, sec-butyl, tert-butyl, amyl, isopentyl or neopentyl, with isopropyl being preferable. The term xe2x80x9clower alkylxe2x80x9d used in the definition of R16, R17, R18, R19 and R20 refers to methyl, ethyl, propyl, butyl, amyl, isopropyl, sec-butyl, tert-butyl or the like.
The term xe2x80x9clinear lower alkoxyxe2x80x9d used in the definition of R1, R2, R3, R4, R5 and R6 refers to linear C1-C6 alkoxy, and examples thereof include methoxy, ethoxy, n-propoxy and n-butoxy. The term xe2x80x9cbranched lower alkoxyxe2x80x9d used therein refers to isopropoxy, sec-butoxy or the like. The term xe2x80x9ccycloalkylxe2x80x9d used in the definition of R7 and R8 refers to C3-C7 cycloalkyl, and examples thereof include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. Further, the term xe2x80x9chalogensxe2x80x9d used in this description refers to fluoro, chloro or bromo.
Specific examples of the above compounds wherein R7 or R8 together with R4 or R6 forms a ring include compounds as described above wherein X is NR7R8, Y is CR9R10R11, R7 and R8 form rings, R10 and R11 are hydrogen, R8 is n-propyl or the like, and R7 and R4 are united to form a ring, and such compounds are represented by, e.g., 
When A, B and D are each carbon, the formula (1-V) can be represented by 
In the definition of Z in the general formula (1-VI), the cases wherein l is 1 or 2, m is 1 and p is 1 are preferable. Specific examples of the compounds according this preferable embodiment include those represented by the formulae: 
Further, it is most desirable that n is 3.
Preferable examples of the compounds represented by the general formula (1-V) include the following compounds: 
The second embodiment of the present invention relates to heterocyclic compounds represented by the following formula (2-I) or physiologically acceptable salts thereof: 
[wherein R1 and R2 are each independently hydrogen, lower alkyl, alkenylalkyl, alkynylalkyl, cycloalkyl, cycloalkylalkyl, lower alkoxyalkyl, aryl, heteroaryl or arylalkyl, or alternatively R1 and R2 may be united to form a 5- to 7-membered cycloalkyl group which is substituted with a lower alkyl group and may contain sulfur, oxygen, sulfinyl, sulfonyl or NR3 (wherein R3 is hydrogen or lower alkyl); the broken line moiety represents a single bond or a double bond; A represents 
and
B represents 
(wherein R6 is hydrogen, lower alkyl, alkenylalkyl, alkynylalkyl, cycloalkyl, cycloalkylalkyl, lower alkoxyalkyl, aryl, heteroaryl, arylalkyl or heteroarylalkyl; R13 is hydrogen, lower alkyl or lower alkoxy; R7 is 
(wherein E is aryl, heteroaryl or 
(wherein R11 and R12 are each hydrogen or lower alkyl; and m is an integer of 1 to 3); and R8 is hydrogen, hydroxyl, lower alkoxy or xe2x80x94NR9R10 (wherein R9 and R10 are each independently hydrogen, hydroxyl, lower alkyl, lower alkoxy, hydroxyalkyl, aryl, hydroxyaryl or heteroaryl, or alternatively R9 and R10 together with the nitrogen atom to which they are bonded may form a ring which may contain nitrogen, oxygen or sulfur))].
Further, the present invention relates also to compounds represented by the general formula (2-II) or (2-III) or physiologically acceptable salts thereof: 
[wherein R1 and R2 are each independently hydrogen, lower alkyl, alkenylalkyl, alkynylalkyl, cycloalkyl, cycloalkylalkyl, lower alkoxyalkyl, aryl, heteroaryl or arylalkyl, or alternatively R1 and R2 may be united to form a 5- to 7-membered cycloalkyl group which is substituted with a lower alkyl group and may contain sulfur, oxygen, sulfinyl, sulfonyl or NR3 (wherein R3 is hydrogen or lower alkyl); the broken line moiety represents a single bond or a double bond; and
B is a group represented by the formula: 
(wherein R6 is hydrogen, lower alkyl, alkenylalkyl, alkynylalkyl, cycloalkyl, cycloalkylalkyl, lower alkoxyalkyl, aryl, heteroaryl, arylalkyl or heteroarylalkyl; R13 is hydrogen, lower alkyl or lower alkoxy; and R7 is 
(wherein E is aryl, heteroaryl or 
(wherein R11 and R12 are each hydrogen or lower alkyl; and m is an integer of 1 to 3); and R8 is hydrogen, hydroxyl, lower alkoxy or xe2x80x94NR9R10 (wherein R9 and R10 are each independently hydrogen, hydroxyl, lower alkyl, lower alkoxy, hydroxyalkyl, aryl, hydroxyaryl or heteroaryl, or alternatively R9 and R10 together with the nitrogen atom to which they are bonded may form a ring which may contain nitrogen, oxygen or sulfur))].
The term xe2x80x9clower alkylxe2x80x9d used in the above definition for the compounds (2-I) to (2-III) according to the present invention refers to linear or branched C1-C6 alkyl, and examples thereof include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, amyl, isopentyl and neopentyl. Among them, methyl, ethyl, propyl and isopropyl are preferable. The term xe2x80x9clower alkoxyxe2x80x9d used in the definition of R8, R9, R10 and R13 refers to methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy or the like. The term xe2x80x9ccycloalkylxe2x80x9d used in the definition of R6 refers to C3-C7 cycloalkyl, and examples thereof include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. The term xe2x80x9ccycloalkylalkylxe2x80x9d used in the definition of R6 refers to one derived from the above cycloalkyl, and representative examples thereof include cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl and cyclohexylethyl. The term xe2x80x9cbridged cyclic hydrocarbylxe2x80x9d refers to adamantyl, adamantylmethyl or the like. The term xe2x80x9carylxe2x80x9d used in the definition of R6, R9 and R10 refers to phenyl, naphthyl or the like, which may be substituted with lower alkyl such as methyl or ethyl, halogeno, lower alkoxy, hydroxyl or the like. The term xe2x80x9chydroxyarylxe2x80x9d used in the definition of R9 and R10 refers to a group comprising an aryl group such as phenyl or naphthyl and a hydroxyl group bonded thereto. The term xe2x80x9carylalkylxe2x80x9d used in the definition of R6 refers to one derived from the above aryl group. Preferable examples thereof include benzyl and phenethyl. The above aryl group may be substituted with lower alkyl such as methyl or ethyl, halogeno, lower alkoxy, hydroxy or the like.
The term xe2x80x9cheteroarylxe2x80x9d used in the definition of R6 refers to a group derived from a heterocycle, and examples thereof include pyridyl, thiazolyl, pyrimidyl, furyl and thienyl.
The term xe2x80x9cheteroarylalkylxe2x80x9d used in the definition of R6 refers to a group derived from the above heteroaryl, and examples thereof include pyridylmethyl and pyridylethyl.
The term xe2x80x9clower alkoxyalkylxe2x80x9d used in the definition of R6 refers to a group derived from the above lower alkoxy, examples thereof including methoxyethoxy, methoxypropoxy and ethoxyethoxy.
As defined above with respect to R9 and R10, R9 and R10 together with the nitrogen atom to which they are bonded may form a ring which may contain nitrogen, oxygen or sulfur. Examples of such a ring include the following: 
Compounds represented by the above general formula (2-I) or physiologically acceptable salts thereof, wherein B represents a substituted, 5- or 6-membered unsaturated heterocyclic structure containing one or two heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, with such a heterocyclic structure including 
[wherein R13 is hydrogen, lower alkyl or lower alkoxy; and R7 is 
(wherein E is heteroaryl or 
(wherein R11 and R12 are each hydrogen or lower alkyl; and m is an integer of 1 to 3); and R8 is xe2x80x94NR9R10 (wherein R9 and R10 are each independently hydroxyaryl)].
Compounds represented by the above general formula (2-II) or (2-III) or physiologically acceptable salts thereof, wherein R1 and R2 are each independently hydrogen, alkenylalkyl, alkylalkyl, cycloalkyl, cycloalkylalkyl, lower alkoxyalkyl, aryl, heteroaryl or arylalkyl, with the cycloalkyl ring optionally containing sulfur, oxygen, sulfinyl, sulfonyl or NR3 (wherein R3 is hydrogen or lower alkyl); and B is a group represented by the formula: 
[wherein R13 is hydrogen, lower alkyl or lower alkoxy; and R7 is 
(wherein E is heteroaryl or 
(wherein R11 and R12 are each independently hydrogen or lower alkyl; and m is an integer of 1 to 3))].
In the present invention, the term xe2x80x9cphysiologically acceptable saltsxe2x80x9d refers to conventional nontoxic salts. Examples thereof include inorganic acid salts such as hydrochloride, hydrobromide, sulfate and phosphate; organic acid salts such as acetate, maleate, oxalate, methanesulfonate, benzenesulfonate and toluenesulfonate; and amino acid salts such as argininate, aspartate and glutamate. Further, some of the carboxylic acid derivatives of the present invention take the form of salts with metals such as Na, K, Ca or Mg, and such salts are also included among the physiologically acceptable salts according to the present invention.
Preparation processes for preparing the compound according to the first embodiment of the present invention will now be described.

(in the above reaction scheme, Rd is as defined above; Rxe2x80x2, Rxe2x80x3 and Rxe2x80x3xe2x80x2 are each alkyl; J is hahogeno; L is H or halogeno; and Rxe2x80x2M is an organometallic reagent).
(i) An N-alkylate represented by the general formula (2) is prepared by reacting the compound (1) with an alkyl halide in the presence of a base. Better results can be attained when potassium carbonate, sodium hydride or the like is used as the base. N,N-Dimethylformamide or tetrahydrofuran can be used as the solvent for this reaction. The reaction temperature may range from 0xc2x0 C. to the boiling point of the solvent, preferably from 0xc2x0 C. to 80xc2x0 C.
(ii) An aldehyde represented by the general formula (3) is prepared from the N-alkylate (2) by the Vilsmeir process or the like.
(iii) An alcohol represented by the general formula (4) is prepared by reacting the aldehyde (3) with an organometallic reagent such as a Grignard reagent, organolithium reagent, organolithium-copper complex or the like. Ethers such as diethyl ether or tetrahydrofuran can be used as the solvent for this reaction. The reaction temperature may range from xe2x88x9278xc2x0 C. to the boiling point of the solvent, preferably from xe2x88x9278xc2x0 C. to 20xc2x0 C.
(iv) A ketone represented by the general formula (5) is prepared by oxidizing the alcohol (4) with a suitable oxidizing agent. The use of activated manganese dioxide, PCC, PDC, Swern oxidizing agent or the like as the oxidizing agent gives good results. A solvent which is not oxidized with the oxidizing agent can be used for this reaction, such a solvent including dichloromethane and acetone. The reaction temperature may range from xe2x88x9278xc2x0 C. to the boiling point of the solvent, preferably from xe2x88x9278xc2x0 C. to 20xc2x0 C.
(v) An acrylic acid derivative represented by the general formula (6) is prepared by subjecting the ketone (5) to the Wittig-Horner reaction or the Horner-Emmons reaction in the presence of a base. Better results can be attained; when sodium hydride, sodium alkoxide, n-butyllithium, potassium t-butoxide or lithium bistrimethylsilylamide is used as the base. The solvent usable in this reaction includes N,N-dimethylformamide, n-hexane, tetrahydrofuran and diethyl ether. The reaction temperature may range from xe2x88x9278xc2x0 C. to the boiling point of the solvent, preferably xe2x88x9278xc2x0 C. to 20xc2x0 C.
(vi) An allyl alcohol represented by the general formula (7) is prepared by reducing the acrylic acid derivative (6) with a suitable reducing agent. Better results can be attained, when diisobutylaluminum hydride or lithium borohydride is used as the reducing agent. Tetrahydrofuran, dichloromethane or the like can be used as the solvent for this reaction. The reaction temperature may range from xe2x88x9278xc2x0 C. to the boiling point of the solvent, preferably from xe2x88x9278xc2x0 C. to 20xc2x0 C.
(vii) An aldehyde represented by the general formula (8) is prepared by oxidizing the allyl alcohol (7) in a similar manner to that employed in the step (iv).
(viii) A trienic carboxylic acid ester represented by the general formula (9) is prepared by subjecting the aldehyde (8) to the Wittig-Horner reaction or the Horner-Emmons reaction in a similar manner to that employed in the step (v).
(ix) A trienic carboxylic acid derivative represented by the general formula (10) is prepared by hydrolyzing the ester (9) in the presence of a base. Better results can be attained, when an aqueous solution of sodium hydroxide, potassium hydroxide or lithium hydroxide is used as the base. Alcohols such as methanol, ethanol and so on can be used as the solvent for this reaction. The reaction temperature may range from 0xc2x0 C. to the boiling point of the solvent, preferably from 20xc2x0 C. to the boiling point of the solvent.

(wherein R and Rxe2x80x2 are each as defined above).
A dienic carboxylic acid ester represented by the general formula (11) is prepared by subjecting the aldehyde (8) to the Wittig-Horner reaction or the Horner-Emmons reaction in the presence of a base. Then, the obtained ester is converted into an aldehyde represented by the general formula (12) by conventional reduction and oxidation. This aldehyde is further subjected to the Witting-Horner reaction or the Horner-Emmons reaction in a similar manner to that described above to give a trienic carboxylic acid ester represented by the general formula (13). This ester is hydrolyzed by a conventional process into a trienic carboxylic acid represented by the general formula (14).

(wherein R and Rxe2x80x2 are each as defined above).
An acrylic acid derivative represented by the general formula (15) is prepared by subjecting the aldehyde (3) to the Wittig-Horner reaction or the Horner-Emmons reaction in the presence of a base. Then, the acid derivative is reduced and oxidized by conventional processes to give an aldehyde represented by the general formula (16). This aldehyde is subjected to the Wittig-Horner reaction or the Horner-Emmons reaction in a similar manner to that described above to give a trienic carboxylic acid ester represented by the general formula (17). A trienic carboxylic acid represented by the general formula (18) is obtained by hydrolyzing this ester in a conventional manner.
Representative processes for preparing the compounds according to the second embodiment of the present invention will now be described.

(in the reaction scheme, A, R6, R7 and broken line are each as defined above; and X is halogen).
A diketone represented by the general formula (1) is prepared by reacting the ketone (2) with an acid chloride (3) in the presence of a base. Better results can be attained when lithium diisopropylamide, lithium bistrimethylsilylamide or the like is used as the base. The solvent usable for this reaction includes ethers such as diethyl ether, tetrahydrofuran and dimethoxyethane. The reaction temperature may range from xe2x88x9278xc2x0 C. to the boiling point of the solvent, preferably xe2x88x9278xc2x0 C. to 20xc2x0 C.
A pyrazole represented by the general formula (4) is prepared by reacting the diketone (1) with hydrazine hydrate, while a pyrazole represented by the general formula (6) is prepared by reacting the diketone (1) with a mono-substituted hydrazine (5) and removing undesirable isomers from the obtained product by crystallization or column chromatography.
Although this reaction can proceed without using any catalyst, it may be accelerated by the addition of an acid useful also as a dehydrating agent, with such an acid including hydrochloric acid, sulfuric acid, acetic acid and polyphosphoric acid.
The solvent for the reaction may, in principle, be any one which is unreactive with hydrazine. Examples of such a solvent include alcohols such as methanol, ethanol and isopropanol; aromatic hydrocarbons such as benzene, toluene and xylene; aprotic solvents such as dimethylformamide and dimethyl sulfoxide; and chlorinated hydrocarbons such as dichloromethane, chloroform and 1,2-dichloroethane. The reaction temperature may range from 0xc2x0 C. to the boiling point of the solvent, preferably from room temperature to the boiling point of the solvent. Alternatively, a compound represented by the general formula (6) can be prepared by reacting the compound (4) with a halide represented by the general formula (7) in the presence of a base and removing simultaneously formed undesirable isomers from the obtained product by crystallization or column chromatography. Examples of the base usable in this reaction include alkali metal compounds such as potassium carbonate, sodium hydride and potassium hydride; and alkali metal alkoxides such as sodium methoxide, sodium ethoxide and potassium t-butoxide. The solvent usable for the reaction includes dimethylformamide, tetrahydrofuran and 1,2-dimethoxyethane. The reaction temperature may range from 0xc2x0 C. to the boiling point of the solvent.

(in the above reaction scheme, R1, R2, R6, R7, A and n are each as defined above).
A compound represented by the general formula (8) is prepared by reacting a ketone represented by the general formula (2) with an aldehyde represented by the general formula (9) in the presence of a catalytic amount of a base to form an alcohol (10), and dehydrating this alcohol in the presence of an acid. The base to be used in the preparation of the alcohol (10) is preferably alkali hydroxide such as sodium hydroxide or potassium hydroxide. The solvent to be used therein includes methanol, ethanol, propanol, tetrahydrofuran and dimethylformamide. The reaction temperature may range from 0xc2x0 C. to the boiling point of the solvent, preferably from 20xc2x0 C. to 40xc2x0 C.
The acid to be used in the above dehydration includes hydrochloric acid, sulfuric acid, p-toluenesulfonic acid, trifluoroacetic acid, oxalic acid and phosphoric acid. The solvent to be used therein includes ethers such as diethyl ether, tetra-hydrofuran, 1,4-dioxane and 1,2-dimethoxyethane; and aromatic hydrocarbons such as benzene, toluene and xylene. The reaction temperature may range from 0xc2x0 C. to the boiling point of the solvent. Some of the compounds (8) can be prepared directly from the compounds (2) without dehydration.
Then, the compound (8) can be converted into a compound (11) by reacting the compound (8) with a catalytic amount of a base in a solvent comprising nitromethane (and, if necessary, tetrahydrofuran, methanol, ethanol or the like, when the compound is difficultly soluble). The base to be used in this reaction includes N-benzyltrimethylammonium hydroxide, triethylamine and diisopropylethylamine. The reaction is conducted at a temperature ranging from 0xc2x0 C. to the boiling point of the solvent, preferably from 0xc2x0 C. to room temperature.
A ketal represented by the general formula (12) is prepared by converting the compound (11) into a xcex3-ketoaldehyde through the Nef reaction (Chem. Rev., 55, 137 (1955)) and converting this ketoaldehyde into a ketal. The conversion into a ketal can be attained by adding a mineral acid such as sulfuric acid or hydrochloric acid to methanol and adding the xcex-ketoaldehyde to the obtained mixture. The reaction temperature may range from xe2x88x9278xc2x0 C. to the boiling point of the solvent, preferably from xe2x88x9240xc2x0 C. to room temperature.
A pyrrole (13) is prepared by reacting the dimethyl ketal (12) with a primary amine represented by the general formula R6xe2x80x94NH2. The solvent to be used in this reaction may be any one inert to the reaction. Preferable examples of such a solvent include aromatic hydrocarbons such as benzene, toluene and xylene; ethers such as tetrahydrofuran and 1,2-dimethoxyethane; and alcohols such as methanol and ethanol. The above reaction can proceed in such a solvent with which an acid is coexistent. The acid to be used is preferably one useful also as a dehydrating agent, and examples of such an acid include hydrochloric acid, sulfuric acid, glacial acetic acid and polyphosphoric acid.
The dimethyl ketal (12) can be converted also into a furan (14) by reacting the with an acid. Sulfuric acid, polyphosphoric acid or the like is used as the acid, and the reaction is conducted at 0 to 100xc2x0 C. Further, a thiophene (15) can be obtained by reacting the ketal (12) with a sulfide such as phosphorus pentasulfide or hydrogen sulfide. The solvent to be used in this reaction includes aromatic hydrocarbons such as benzene, toluene and xylene, and pyridine, while the reaction temperature may range from 0xc2x0 C. to the boiling point of the solvent, preferably from 50xc2x0 C. to the boiling point of the solvent.
Pharmacological Experimental Examples will now be described to illustrate the effects of the compounds according to the second embodiment of the present invention.
It is known that all-trans retinoic acid receptors (retinoic acid receptor: RAR) are is present in the nuclei of HL60 cells (Clara Nervi et al., Proc. Natl. Acad. Sci. U.S.A. 86, 5854(1989)). Therefore, the specific binding of all-trans retinoic acid for RAR was determined by the use of the nuclear extract fraction of HL60, and each test compound was examined for the ability to bind RAR by determining the inhibition against the specific binding.
The nuclear extract fraction was prepared as follows.
HL60 cells (5xc3x97108) were suspended in 15 ml of solution A (sodium phosphate (pH7.4): 5 mM, monothioglycerol: 10 mM, glycerol: 10% (v/v), phenylmethylsulfonyl fluoride (PMSF): 1 mM, aprotinin: 10 xcexcg/ml, and leupeptin: 25 xcexcg/ml). The obtained suspension was homogenized by the use of a homogenizer and centrifuged to remove the resulting supernatant. The sediment thus formed was suspended in 15 ml of solution B (Tris-HCl(pH8.5): 10 mM, monothioglycerol: 10 mM, glycerol: 10% (v/v), PMSF: 1 mM, aprotinin: 10 xcexcg/ml, leupeptin: 25 xcexcg/ml, and KCl: 0.8 M). The obtained suspension was allowed to stand at 4xc2x0 C. for one hour, and subjected to ultracentrifugation (100,000xc3x97g, 4xc2x0 C., 1 hr). The obtained supernatant was stored as the nuclear extract fraction in a frozen state at xe2x88x9280xc2x0 C. until the use (METHODS IN ENZYMOLOGY, 189, 248).
The receptor binding assay was conducted as follows.
180 xcexcl of the above fraction and 10 xcexcl of a dilution of all-trans retinoic acid or a test compound were added to each well of a 96-well plate made of polypropylene, followed by the addition of 10 xcexcl of 10 nM3H-all-trans retinoic acid. The resulting plate was allowed to stand at 4xc2x0 C. for 16 hours. A solution containing 3% of charcoal and 0.3% of dextran was added to the resulting reaction mixture. The mixture thus obtained was centrifuged to remove free 3H-all-trans retinoic acid. The radioactivity of the resulting supernatant was determined by the use of a scintillation counter. The specific binding of 3H-all-trans retinoic acid for RAR was determined by assuming the radioactivity found when 200 times as much all-trans retinoic acid was added to be the non-specific binding and subtracting it from the radioactivity determined above. The compounds which will be described below inhibited the binding of 3H-all-trans retinoic acid dependently on the concentration. The 50% inhibitory concentration of each test compound was calculated and the results are given in Table 1.
It is known that human promyelocytic leukemia cells HL60 differentiate into granulocyte-like cells in the presence of all-trans retinoic acid (Breitman, T., Selonick, S., and Collins, S., Proc. Natl. Acad. Sci. U.S.A. 77, 2936(1980)). In general, cells allow specific differentiation antigens to be expressed on the cell surfaces when they have achieved differentiation. When HL60 cells differentiate into granulocyte-like cells, CD11b which is a granulocyte/monocyte discriminating antigen is expressed on the cell surfaces (Fontana, J A., Reppuci, A., Durham, J P., and Mirand, D., Cancer Res. 46, 2469-2473 (1986)). The antagonism of a test compound against the differentiation into granulocyte-like cells induced by all-trans retinoic acid was studied by utilizing this phenomenon.
HL60 cells were cultured and maintained in a medium prepared by adding 10% of inactivated fetal bovine serum, 1 mM of sodium pyridinecarboxylate, 50 xcexcM of xcex2-mercaptoethanol, 100 IU/ml of penicillin and 100 xcexcg/ml of streptomycin to RPMI1640 (culture medium formulated by Rosewell Park Memorial Institute).
An HL60 cell suspension (1xc3x97105 cells/ml) was put in a 48-well plate in an amount of one ml per unit well, followed by the addition of all-trans retinoic acid in a concentration of 10 mM and a retinoid antagonist in various concentrations. The resulting mixtures were cultured in a 5% CO2-air incubator for 5 days. After the completion of the culture, the cells in each well was recovered into a test tube, followed by the addition of an FITC-labeled monoclonal antibody against CD11b (which is a specific antigen against glanulocytes and monocytes). The resulting cell suspension was fixed with 0.2% paraformaldehyde. The fixed cell suspension thus obtained was examined for the content of CD11b-positive cells in the HL60 cell population of each well by flow cytometry (Miller, L. J., Schwarting, R., and Springer, T A., J. Immunol. 137, 2891-2900 (1986)). The compounds which will be described below lowered the content of CD11b-positive cells induced by 10 nM all-trans retinoic acid dependently on the concentration. The 50% inhibitory concentration of each test compound was calculated and the results are given in Table 1.
It is apparent from the results of the above Experimental Examples that the compounds of the present invention have an extremely high ability to bind RARs and an antagonism against all-trans retinoic acid. Therefore, the compounds of the present invention can be expected to be efficacious against the following diseases:
various cornification anomalies, psoriasis, acne, leukoplakia, and xeroderma pigmentosum;
various alopeciae such as alopecia areata, seborrheic alopecia and cachectic alopecia;
postmenopausal osteoporosis, senile osteoporosis, idiopathic osteoporosis, diabetic osteopenia, rheumatoid osteopenia, renal osteomalacia and ectopic hyperostosis;
rheumatoid arthritis, osteoarthritis, and shoulder periarthritis;
activation of immunofunction in immunodefficiencies, infectious diseases in hypofunction or of fetus with cytomegalovirus, and opportunistic infection;
hyperthyroidism;
squamous cell carcinoma, bladder cancer, lung cancer, esophageal carcinoma, and head and neck cancer;
hyperkalemia; and
pulmonary fibrosis, hepatic fibrosis, and hepatic cirrhosis.
The compounds of the present invention may be orally administered as preventive or therapeutic agents for these diseases in the form of tablet, powder, granule, capsule, syrup or the like, or may be parenterally administered in the form of suppository, injection, external preparation or drop.
Pharmaceutical preparations for oral or parenteral administration according to the present invention can be formulated by the use of conventional pharmaceutically acceptable carriers in a conventional manner.
Subcutaneous, intramuscular or intravenous injections or dropping injections according to the present invention can be formulated by conventional processes of adding a pH regulator, buffer, stabilizer or solubilizing agent to a base at need and, if necessary, freeze-drying the obtained mixture.